Famotidine is a pharmaceutical agent excellent in inhibitory action of gastric acid secretion based on a histamine H2-receptor antagonistic action and generally used in the form of an oral or injection preparation as an agent for treating gastric ulcer, duodenal ulcer, and other digestive diseases (cf. Merck Index thirteen edition, page 696 and so on). With regard to famotidine injection preparations, two kinds of preparations, i.e., a solution preparation and a freeze-dried preparation are present. The solution preparation is commercially available in United States and Europe for intravenous administration, and the freeze-dried preparation is commercially available in Japan as an administration system mainly for intravenous administration and is also used for intramuscular administration. However, an injection solution capable of being preserved at room temperature and capable of being administered intramuscularly is not commercially available.
Famotidine is a basic compound having a pKa value of about 7.1, and it is soluble in water but exhibits a low stability at an acidic side while the solubility extremely decreases at a neutral range where the stability is high.
Hitherto, in the vicinity of a neutral pH range where famotidine exhibits a good stability, various attempts to develop an injection preparation wherein famotidine is solubilized and stable have been made. However, in the case of intramuscular administration, since the administration is physically difficult when a dose is a large amount, the liquid amount to be administered is limited. Usually, the amount is about 4 ml at most. A famotidine injection solution for intramuscular administration requires that solubilization and stabilization of famotidine are achieved even in a small liquid amount (e.g., 3 ml) and further the absorbability does not decreases. Such famotidine injection solution capable of being administered intramuscularly is not yet known.
With regard to famotidine injection preparations, the following technologies are known.
JP-B-63-65047 (or CA1184495) describes the following: a low water-solubility (solubility of 0.1 w/v % or lower) of famotidine makes development of its injection preparation difficult; selection of a substance capable of solubilizing famotidine in a high concentration is necessary for developing the injection preparation; although selection of an acid is considered, selection of an acid capable of not only solubilizing famotidine but also stabilizing is necessary since it is unstable in an acidic region; a stable injection preparation dissolving famotidine in a high concentration (10 mg/ml) can be first provided when a specific acid, L-aspartic acid is mixed; and so forth. The famotidine injection preparation in clinical use at present is a freeze-dried preparation produced based on the patented invention and it main administration route is intravenous administration. However, in general, a freeze-dried preparation should be prepared before use employing a physiologically allowable dissolution liquid such as physiological saline, and thus it can be said that the preparation is a preparation accompanied by vexatious complication.
In this connection, the pH of the solution obtained by dissolving the freeze-dried preparation in water for injection is about 5.2.
In addition, U.S. Pat. No. 5,650,421 discloses an injection preparation wherein the concentration of famotidine or it salt is from 0.1 mg/ml to 0.8 mg/ml, the pH is adjusted to from 5.7 to 6.4 by adding an acid such as L-aspartic acid, and the preparation is mixed with physiological saline in advance. However, when application to a preparation capable of being administered intramuscularly is considered, a preparation having a high concentration which is adjusted to a volume for intramuscular administration requiring a minimum volume, i.e., it is necessary to be a preparation having a concentration of 6.67 mg/ml or higher (a concentration calculated based on the assumption that the liquid amount capable for intramuscular administration is about 3 ml or less and 20 mg of famotidine, which is a single dose thereof, is contained).
JP-A-11-193233 describes a famotidine injection preparation having a pH of about 5.5 to about 7.5 which contains famotidine or its salt in an amount of about 1 mg/ml to about 40 mg/ml in terms of famotidine, especially which comprises famotidine or its salt, an acidic substance, and a water-soluble non-aqueous solvent.
The above invention using a water-soluble non-aqueous solvent is an excellent technology which solves the above problem and especially achieves a drug concentration of about 6.67 mg/ml or higher enabling intramuscular administration and a long-term stability at room temperature, but owing to the characteristic property of the water-soluble non-aqueous solvent such as polyethylene glycol, propylene glycol, or glycerin, viscosity of the formulated drug solution increases and its absorption after intramuscular administration is delayed as compared with the conventional preparation because of the factors such as the viscosity, so that the improvement has been desired.
Thus, a famotidine injection solution containing famotidine or its salt in a high concentration of from 1 to 40 mg/ml, having a good stability, and excellent in absorbability after administration, which may be capable of being administered intramuscularly, has been highly desired.